NTRK fusion-positive cancers and TRK inhibitor therapy

Abstract

NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.

Key points

  • NTRK fusions, encoding TRK fusion proteins, are oncogenic drivers of a wide variety of adult and paediatric tumours, supporting a basket trial approach to drug development.

  • These alterations are found at high frequencies (up to or greater than 90%) in rare cancer types (secretory breast carcinoma, mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma and infantile fibrosarcoma) and at lower frequencies (commonly <1%) in a range of other tumour types.

  • NTRK fusions are clinically actionable: first-generation TRK tyrosine kinase inhibitors (larotrectinib or entrectinib) result in histology-agnostic responses in both adult and paediatric patients with NTRK fusion-positive cancers.

  • Resistance to TRK inhibition can be mediated by the acquisition of NTRK kinase domain mutations, including solvent-front and gatekeeper mutations; second-generation TRK inhibitors have been developed to overcome these mechanisms of resistance.

  • First-generation TRK inhibitors are generally well-tolerated and, with consideration of the biological roles of TRK receptors in normal development and adulthood, the occasional on-target adverse effects are predictable.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timeline of key advances relating to the biology and therapeutic targeting of TRK signalling.
Fig. 2: TRK biology and signalling in the nervous system.
Fig. 3: Activating mechanisms of NTRK fusions.
Fig. 4: Distribution and frequency of NTRK fusions in adult and paediatric tumours.
Fig. 5: Mechanisms of acquired resistance to TRK inhibitors and profiles of TRK inhibitor activity.
Fig. 6: Consequences of loss, decreased activity or inhibition of TRK.

References

  1. 1.

    Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).

    PubMed  Google Scholar 

  2. 2.

    Geyer, C. E. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 (2006).

    CAS  PubMed  Google Scholar 

  3. 3.

    Planchard, D. et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet. Oncol. 17, 984–993 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Shaw, A. T. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 1963–1971 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  PubMed  Google Scholar 

  6. 6.

    Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014).

    PubMed  Google Scholar 

  7. 7.

    Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hyman, D. M. et al. AKT inhibition in solid tumors with AKT1 mutations. J. Clin. Oncol. 35, 2251–2259 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Drilon, A. et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase i trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 7, 400–409 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Pulciani, S. et al. Oncogenes in solid human tumours. Nature 300, 539–542 (1982).

    CAS  PubMed  Google Scholar 

  13. 13.

    Martin-Zanca, D., Hughes, S. H. & Barbacid, M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 319, 743–748 (1986).

    CAS  PubMed  Google Scholar 

  14. 14.

    Martin-Zanca, D., Oskam, R., Mitra, G., Copeland, T. & Barbacid, M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol. Cell. Biol. 9, 24–33 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Klein, R., Jing, S. Q., Nanduri, V., O’Rourke, E. & Barbacid, M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65, 189–197 (1991).

    CAS  PubMed  Google Scholar 

  16. 16.

    Kaplan, D. R., Hempstead, B. L., Martin-Zanca, D., Chao, M. V. & Parada, L. F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252, 554–558 (1991).

    CAS  PubMed  Google Scholar 

  17. 17.

    Klein, R., Parada, L. F., Coulier, F. & Barbacid, M. trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. EMBO J. 8, 3701–3709 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lamballe, F., Klein, R. & Barbacid, M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66, 967–979 (1991).

    CAS  PubMed  Google Scholar 

  19. 19.

    Davies, A. M. et al. Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. J. Neurosci. 13, 4961–4967 (1993).

    CAS  PubMed  Google Scholar 

  20. 20.

    Soppet, D. et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65, 895–903 (1991).

    CAS  PubMed  Google Scholar 

  21. 21.

    Deinhardt, K. & Chao, M. V. Trk receptors. Handb. Exp. Pharmacol. 220, 103–119 (2014).

    CAS  PubMed  Google Scholar 

  22. 22.

    Snider, W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638 (1994).

    PubMed  Google Scholar 

  23. 23.

    Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Arevalo, J. C. et al. A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation. Oncogene 20, 1229–1234 (2001).

    CAS  PubMed  Google Scholar 

  25. 25.

    Zaccaro, M. C., Ivanisevic, L., Perez, P., Meakin, S. O. & Saragovi, H. U. p75 Co-receptors regulate ligand-dependent and ligand-independent Trk receptor activation, in part by altering Trk docking subdomains. J. Biol. Chem. 276, 31023–31029 (2001).

    CAS  PubMed  Google Scholar 

  26. 26.

    Barbacid, M. The Trk family of neurotrophin receptors. J. Neurobiol. 25, 1386–1403 (1994).

    CAS  PubMed  Google Scholar 

  27. 27.

    Huang, E. J. & Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).

    CAS  PubMed  Google Scholar 

  28. 28.

    Clary, D. O. & Reichardt, L. F. An alternatively spliced form of the nerve growth factor receptor TrkA confers an enhanced response to neurotrophin 3. Proc. Natl Acad. Sci. USA 91, 11133–11137 (1994).

    CAS  PubMed  Google Scholar 

  29. 29.

    Brodeur, G. M. et al. Trk receptor expression and inhibition in neuroblastomas. Clin. Cancer Res. 15, 3244–3250 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Tacconelli, A. et al. TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6, 347–360 (2004).

    CAS  PubMed  Google Scholar 

  31. 31.

    Tacconelli, A., Farina, A. R., Cappabianca, L., Gulino, A. & Mackay, A. R. Alternative TrkAIII splicing: a potential regulated tumor-promoting switch and therapeutic target in neuroblastoma. Future Oncol. 1, 689–698 (2005).

    CAS  PubMed  Google Scholar 

  32. 32.

    Strohmaier, C., Carter, B. D., Urfer, R., Barde, Y. A. & Dechant, G. A splice variant of the neurotrophin receptor trkB with increased specificity for brain-derived neurotrophic factor. EMBO J. 15, 3332–3337 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Boeshore, K. L., Luckey, C. N., Zigmond, R. E. & Large, T. H. TrkB isoforms with distinct neurotrophin specificities are expressed in predominantly nonoverlapping populations of avian dorsal root ganglion neurons. J. Neurosci. 19, 4739–4747 (1999).

    CAS  PubMed  Google Scholar 

  34. 34.

    Luberg, K., Wong, J., Weickert, C. S. & Timmusk, T. Human TrkB gene: novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development. J. Neurochem. 113, 952–964 (2010).

    CAS  PubMed  Google Scholar 

  35. 35.

    Valenzuela, D. M. et al. Alternative forms of rat TrkC with different functional capabilities. Neuron 10, 963–974 (1993).

    CAS  PubMed  Google Scholar 

  36. 36.

    Stoilov, P., Castren, E. & Stamm, S. Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem. Biophys. Res. Commun. 290, 1054–1065 (2002).

    CAS  PubMed  Google Scholar 

  37. 37.

    Tsoulfas, P., Stephens, R. M., Kaplan, D. R. & Parada, L. F. TrkC isoforms with inserts in the kinase domain show impaired signaling responses. J. Biol. Chem. 271, 5691–5697 (1996).

    CAS  PubMed  Google Scholar 

  38. 38.

    Esteban, P. F. et al. A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin. J. Cell Biol. 173, 291–299 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ohira, K. et al. A truncated tropomyosin-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1. J. Neurosci. 25, 1343–1353 (2005).

    CAS  PubMed  Google Scholar 

  40. 40.

    Cunningham, M. E. & Greene, L. A. A function-structure model for NGF-activated TRK. EMBO J. 17, 7282–7293 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Reichardt, L. F. Neurotrophin-regulated signalling pathways. Phil. Trans. R. Soc. Series B Biol. Sci. 361, 1545–1564 (2006).

    CAS  Google Scholar 

  42. 42.

    Minichiello, L. et al. Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. Neuron 21, 335–345 (1998).

    CAS  PubMed  Google Scholar 

  43. 43.

    Postigo, A. et al. Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons. Genes Dev. 16, 633–645 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Wai, D. H. et al. The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene 19, 906–915 (2000).

    CAS  PubMed  Google Scholar 

  45. 45.

    Barbacid, M., Lamballe, F., Pulido, D. & Klein, R. The trk family of tyrosine protein kinase receptors. Biochim. Biophys. Acta 1072, 115–127 (1991).

    CAS  PubMed  Google Scholar 

  46. 46.

    Levi-Montalcini, R. The nerve growth factor: thirty-five years later. Biosci. Rep. 7, 681–699 (1987).

    CAS  PubMed  Google Scholar 

  47. 47.

    Cohen, S., Levi-Montalcini, R. & Hamburger, V. A. Nerve growth-stimulating factor isolated from sarcom as 37 and 180. Proc. Natl Acad. Sci. USA 40, 1014–1018 (1954).

    CAS  PubMed  Google Scholar 

  48. 48.

    Frade, J. M. & Barde, Y. A. Nerve growth factor: two receptors, multiple functions. Bioessays 20, 137–145 (1998).

    CAS  PubMed  Google Scholar 

  49. 49.

    Patel, T. D., Jackman, A., Rice, F. L., Kucera, J. & Snider, W. D. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 25, 345–357 (2000).

    CAS  PubMed  Google Scholar 

  50. 50.

    Teng, H. K. et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 25, 5455–5463 (2005).

    CAS  PubMed  Google Scholar 

  51. 51.

    Mahadeo, D., Kaplan, L., Chao, M. V. & Hempstead, B. L. High affinity nerve growth factor binding displays a faster rate of association than p140trk binding. Implications for multi-subunit polypeptide receptors. J. Biol. Chem. 269, 6884–6891 (1994).

    CAS  PubMed  Google Scholar 

  52. 52.

    Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F. & Chao, M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350, 678–683 (1991).

    CAS  PubMed  Google Scholar 

  53. 53.

    Bibel, M., Hoppe, E. & Barde, Y. A. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J. 18, 616–622 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Makkerh, J. P. et al. p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation. EMBO Rep. 6, 936–941 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Eggert, A., Sieverts, H., Ikegaki, N. & Brodeur, G. M. p75 mediated apoptosis in neuroblastoma cells is inhibited by expression of TrkA. Med. Pediatr. Oncol. 35, 573–576 (2000).

    CAS  PubMed  Google Scholar 

  56. 56.

    Rabizadeh, S. et al. Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348 (1993).

    CAS  PubMed  Google Scholar 

  57. 57.

    Geiger, T. R., Song, J. Y., Rosado, A. & Peeper, D. S. Functional characterization of human cancer-derived TRKB mutations. PLOS ONE 6, e16871 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Harada, T. et al. Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin. Cancer Res. 17, 2638–2645 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Marchetti, A. et al. Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung. Hum. Mut. 29, 609–616 (2008).

    CAS  PubMed  Google Scholar 

  60. 60.

    Miranda, C., Mazzoni, M., Sensi, M., Pierotti, M. A. & Greco, A. Functional characterization of NTRK1 mutations identified in melanoma. Genes Chromosomes Cancer 53, 875–880 (2014).

    CAS  PubMed  Google Scholar 

  61. 61.

    Tomasson, M. H. et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 111, 4797–4808 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Reuther, G. W., Lambert, Q. T., Caligiuri, M. A. & Der, C. J. Identification and characterization of an activating TrkA deletion mutation in acute myeloid leukemia. Mol. Cell. Biol. 20, 8655–8666 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Eggert, A. et al. Expression of the neurotrophin receptor TrkA down-regulates expression and function of angiogenic stimulators in SH-SY5Y neuroblastoma cells. Cancer Res. 62, 1802–1808 (2002).

    CAS  PubMed  Google Scholar 

  64. 64.

    Lagadec, C. et al. TrkA overexpression enhances growth and metastasis of breast cancer cells. Oncogene 28, 1960–1970 (2009).

    CAS  PubMed  Google Scholar 

  65. 65.

    Lange, A. M. & Lo, H. W. Inhibiting TRK proteins in clinical cancer therapy. Cancers 10, 105 (2018).

    PubMed Central  Google Scholar 

  66. 66.

    Rajan, N. et al. Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours. Oncogene 30, 4243–4260 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Nakagawara, A., Azar, C. G., Scavarda, N. J. & Brodeur, G. M. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol. Cell. Biol. 14, 759–767 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Evans, A. E. et al. Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts. Clin. Cancer Res. 5, 3594–3602 (1999).

    CAS  PubMed  Google Scholar 

  69. 69.

    Evans, A. E. et al. Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB. Med. Pediatr. Oncol. 36, 181–184 (2001).

    CAS  PubMed  Google Scholar 

  70. 70.

    Minturn, J. E. et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. Cancer Chemother. Pharmacol. 68, 1057–1065 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Vaishnavi, A., Le, A. T. & Doebele, R. C. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 5, 25–34 (2015).

    CAS  PubMed  Google Scholar 

  72. 72.

    Schram, A. M., Chang, M. T., Jonsson, P. & Drilon, A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat. Rev. Clin. Oncol. 14, 735–748 (2017).

    CAS  PubMed  Google Scholar 

  73. 73.

    Coulier, F., Martin-Zanca, D., Ernst, M. & Barbacid, M. Mechanism of activation of the human trk oncogene. Mol. Cell. Biol. 9, 15–23 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Knezevich, S. R., McFadden, D. E., Tao, W., Lim, J. F. & Sorensen, P. H. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat. Genet. 18, 184–187 (1998).

    CAS  PubMed  Google Scholar 

  75. 75.

    Hechtman, J. F. et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am. J. Surg. Pathol. 41, 1547–1551 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Singh, D. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Borrello, M. G. et al. The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins. Oncogene 9, 1661–1668 (1994).

    CAS  PubMed  Google Scholar 

  78. 78.

    Miranda, C., Greco, A., Miele, C., Pierotti, M. A. & Van Obberghen, E. IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1. J. Cell. Physiol. 186, 35–46 (2001).

    CAS  PubMed  Google Scholar 

  79. 79.

    Ranzi, V. et al. The signaling adapters fibroblast growth factor receptor substrate 2 and 3 are activated by the thyroid TRK oncoproteins. Endocrinology 144, 922–928 (2003).

    CAS  PubMed  Google Scholar 

  80. 80.

    Jin, W. et al. Cellular transformation and activation of the phosphoinositide-3-kinase-Akt cascade by the ETV6-NTRK3 chimeric tyrosine kinase requires c-Src. Cancer Res. 67, 3192–3200 (2007).

    CAS  PubMed  Google Scholar 

  81. 81.

    Tognon, C. E. et al. A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation. Oncogene 31, 1334–1340 (2012).

    CAS  PubMed  Google Scholar 

  82. 82.

    Drilon, A. et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann. Oncol. 27, 920–926 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Vaishnavi, A. et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat. Med. 19, 1469–1472 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Vaishnavi, A. et al. EGFR mediates responses to small-molecule drugs targeting oncogenic fusion kinases. Cancer Res. 77, 3551–3563 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Chen, S. et al. A new ETV6-NTRK3 cell line model reveals MALAT1 as a novel therapeutic target - a short report. Cell. Oncol. 41, 93–101 (2018).

    CAS  Google Scholar 

  86. 86.

    Cook, P. J. et al. Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target. Nat. Commun. 8, 15987 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Roberts, K. G. et al. ETV6-NTRK3 induces aggressive acute lymphoblastic leukemia highly sensitive to selective TRK inhibition. Blood 132, 861–865 (2018).

    CAS  PubMed  Google Scholar 

  88. 88.

    Witte, K. et al. TFG-1 function in protein secretion and oncogenesis. Nat. Cell Biol. 13, 550–558 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Amatu, A., Sartore-Bianchi, A. & Siena, S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1, e000023 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Halalsheh, H. et al. Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma. Pediat. Blood Cancer 65, e27271 (2018).

    Google Scholar 

  91. 91.

    Davis, J. L. et al. Infantile NTRK-associated mesenchymal tumors. Pediatr. Dev. Pathol. 21, 68–78 (2018).

    PubMed  Google Scholar 

  92. 92.

    Laetsch, T. W. et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet. Oncol. 19, 705–714 (2018).

    CAS  PubMed  Google Scholar 

  93. 93.

    Tognon, C. et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2, 367–376 (2002).

    CAS  PubMed  Google Scholar 

  94. 94.

    Taylor, J. et al. Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies. J. Clin. Invest. 31, 3819–3825 (2018).

    Google Scholar 

  95. 95.

    Benayed, R. et al. Comprehensive detection of targetable fusions in lung adenocarcinomas by complementary targeted DNAseq and RNAseq assays. J. Clin. Oncol. 36, 12076–12076 (2018).

    Google Scholar 

  96. 96.

    Drilon, A. et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 7, 963–972 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Russo, M. et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 6, 36–44 (2016).

    CAS  PubMed  Google Scholar 

  98. 98.

    Rudzinski, E. R. et al. Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. Am. J. Surg. Pathol. 42, 927–935 (2018).

    PubMed  Google Scholar 

  99. 99.

    Menichincheri, M. et al. Discovery of entrectinib: a new 3-aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (pan-TRKs) inhibitor. J. Med. Chem. 59, 3392–3408 (2016).

    CAS  PubMed  Google Scholar 

  100. 100.

    Doebele, R. C. et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 5, 1049–1057 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Kazandjian, D. et al. Benefit-risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive, metastatic non-small cell lung cancer. Oncol. 21, 974–980 (2016).

    Google Scholar 

  102. 102.

    Malik, S. M. et al. U. S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive. Clin. Cancer Res. 20, 2029–2034 (2014).

    CAS  PubMed  Google Scholar 

  103. 103.

    Singh, H. et al. U. S. Food and Drug Administration approval: cabozantinib for the treatment of advanced renal cell carcinoma. Clin. Cancer Res. 23, 330–335 (2017).

    CAS  PubMed  Google Scholar 

  104. 104.

    Shamroe, C. L. & Comeau, J. M. Ponatinib: a new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann. Pharmacother. 47, 1540–1546 (2013).

    CAS  PubMed  Google Scholar 

  105. 105.

    Karimi-Shah, B. A. & Chowdhury, B. A. Forced vital capacity in idiopathic pulmonary fibrosis — FDA review of pirfenidone and nintedanib. N. Engl. J. Med. 372, 1189–1191 (2015).

    PubMed  Google Scholar 

  106. 106.

    Zou, H. Y. et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 67, 4408–4417 (2007).

    CAS  PubMed  Google Scholar 

  107. 107.

    Christensen, J. G. et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol. Cancer Ther. 6, 3314–3322 (2007).

    CAS  PubMed  Google Scholar 

  108. 108.

    Cui, J. J. et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem. 54, 6342–6363 (2011).

    CAS  PubMed  Google Scholar 

  109. 109.

    Bergethon, K. et al. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 30, 863–870 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Bowles, D. W., Kessler, E. R. & Jimeno, A. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib). Drugs Today (Barc) 47, 857–868 (2011).

    CAS  Google Scholar 

  111. 111.

    O’Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412 (2009).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Fuse, M. J. et al. Mechanisms of resistance to NTRK inhibitors and therapeutic strategies in NTRK1-rearranged cancers. Mol. Cancer Ther. 16, 2130–2143 (2017).

    CAS  PubMed  Google Scholar 

  113. 113.

    Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008).

    CAS  PubMed  Google Scholar 

  114. 114.

    Mok, S., Duffy, C., Du, R. & Allison, J. P. Increase antitumor activity of immunotherapy by blocking colony stimulating factor 1 receptor and tropomyosin receptor kinase [abstract]. Cancer Immunol. Res. 4 (Suppl), A146 (2016).

    Google Scholar 

  115. 115.

    Patwardhan, P. P., Ivy, K. S., Musi, E., de Stanchina, E. & Schwartz, G. K. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget 7, 4093–4109 (2016).

    PubMed  Google Scholar 

  116. 116.

    Smith, K. M. et al. Anti-tumor activity of entrectinib, a pan-TRK, ROS1 and ALK inhibitor, in ETV6-NTRK3-positive acute myeloid leukemia. Mol. Cancer Ther. 17, 455–463 (2017).

    PubMed  Google Scholar 

  117. 117.

    Kiga, M. et al. Preclinical characterization and antitumor efficacy of DS-6051b, a novel, orally available small molecule tyrosine kinase inhibitor of ROS1 and NTRKs. Eur. J. Cancer 69, S35–S36 (2016).

    Google Scholar 

  118. 118.

    Smith, B. D. et al. Altiratinib inhibits tumor growth, invasion, angiogenesis, and microenvironment-mediated drug resistance via balanced inhibition of MET, TIE2, and VEGFR2. Mol. Cancer Ther. 14, 2023–2034 (2015).

    CAS  PubMed  Google Scholar 

  119. 119.

    Smith, B. D. et al. Altiratinib is a potent inhibitor of TRK kinases and is efficacious in TRK-fusion driven cancer models [abstract]. Cancer Res. 75, 790 (2015).

    Google Scholar 

  120. 120.

    Kawada, I. et al. Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer. Cancer Res. 74, 884–895 (2014).

    CAS  PubMed  Google Scholar 

  121. 121.

    Yan, S. B. et al. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Invest. New Drugs 36, 536–544 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Konicek, B. W. et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget 9, 13796–13806 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Yan, S. B. et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest. New Drugs 31, 833–844 (2013).

    CAS  PubMed  Google Scholar 

  124. 124.

    Katayama, R. et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci.Transl Med. 4, 120ra117 (2012).

    Google Scholar 

  125. 125.

    Awad, M. M., Engelman, J. A. & Shaw, A. T. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N. Engl. J. Med. 369, 1173 (2013).

    CAS  PubMed  Google Scholar 

  126. 126.

    Kim, S. et al. Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J. Thorac. Oncol. 8, 415–422 (2013).

    CAS  PubMed  Google Scholar 

  127. 127.

    Zhai, D., Deng, W., Huang, J., Rogers, E. & Cui, J. J. TPX-0005, an ALK/ROS1/TRK inhibitor, overcomes multiple resistance mechanisms by targeting SRC/FAK signaling [abstract]. Cancer Res. 77, 3161 (2017).

    Google Scholar 

  128. 128.

    Kozaki, R., Yoshizawa, T., Tsukamoto, K., Kato, H. & Kawabata, K. A potent and selective TRK inhibitor ONO-5390556, shows potent antitumor activity against both TRK-rearranged cancers and the resistant mutants [abstract]. Cancer Res. 76, 2954A (2016).

    Google Scholar 

  129. 129.

    Drilon, A. E. et al. A phase 1 study of the next-generation ALK/ROS1/TRK inhibitor ropotrectinib (TPX-0005) in patients with advanced ALK/ROS1/NTRK + cancers (TRIDENT-1). J. Clin. Oncol. 36, 2513 (2018).

    Google Scholar 

  130. 130.

    Smeyne, R. J. et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368, 246–249 (1994).

    CAS  PubMed  Google Scholar 

  131. 131.

    Klein, R. et al. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75, 113–122 (1993).

    CAS  PubMed  Google Scholar 

  132. 132.

    Klein, R. et al. Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nature 368, 249–251 (1994).

    CAS  PubMed  Google Scholar 

  133. 133.

    Wagner, N. et al. Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms’ tumor transcription factor Wt1. Genes Dev. 19, 2631–2642 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Tessarollo, L. et al. Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis. Proc. Natl Acad. Sci. USA 94, 14776–14781 (1997).

    CAS  PubMed  Google Scholar 

  135. 135.

    Kermani, P. & Hempstead, B. Brain-derived neurotrophic factor: a newly described mediator of angiogenesis. Trends Cardiovasc. Med. 17, 140–143 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Dissen, G. A. et al. A role for trkA nerve growth factor receptors in mammalian ovulation. Endocrinology 137, 198–209 (1996).

    CAS  PubMed  Google Scholar 

  137. 137.

    Kermani, P. et al. Neurotrophins promote revascularization by local recruitment of TrkB + endothelial cells and systemic mobilization of hematopoietic progenitors. J. Clin. Invest. 115, 653–663 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Kawamura, K., Kawamura, N., Mulders, S. M., Sollewijn Gelpke, M. D. & Hsueh, A. J. Ovarian brain-derived neurotrophic factor (BDNF) promotes the development of oocytes into preimplantation embryos. Proc. Natl Acad. Sci. USA 102, 9206–9211 (2005).

    CAS  PubMed  Google Scholar 

  139. 139.

    Greco, A., Villa, R., Fusetti, L., Orlandi, R. & Pierotti, M. A. The Gly571Arg mutation, associated with the autonomic and sensory disorder congenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor. J. Cell. Physiol. 182, 127–133 (2000).

    CAS  PubMed  Google Scholar 

  140. 140.

    Indo, Y. et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat. Genet. 13, 485–488 (1996).

    CAS  PubMed  Google Scholar 

  141. 141.

    Yeo, G. S. et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat. Neurosci. 7, 1187–1189 (2004).

    CAS  PubMed  Google Scholar 

  142. 142.

    Xu, B. et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 6, 736–742 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Richardson, C. A. & Leitch, B. Phenotype of cerebellar glutamatergic neurons is altered in stargazer mutant mice lacking brain-derived neurotrophic factor mRNA expression. J. Comparative Neurol. 481, 145–159 (2005).

    CAS  Google Scholar 

  144. 144.

    Ashraf, S., Bouhana, K. S., Pheneger, J., Andrews, S. W. & Walsh, D. A. Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis. Arthritis Res. Ther. 18, 97 (2016).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Hirose, M., Kuroda, Y. & Murata, E. NGF/TrkA signaling as a therapeutic target for pain. Pain Pract. 16, 175–182 (2016).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank A. Drilon, S. Misale and C. Verma for assisting with the creation and design of the figures in this article. The work of the authors is supported by Cycle for Survival and the National Institutes of Health awards P30 CA008748 and R01CA226864. E.C. is a recipient of a MSK Society Scholar Prize. Given the space limitations of this review, the authors apologize for their inability to cite everyone who has contributed to this field of inquiry.

Reviewer information

Nature Reviews Clinical Oncology thanks T. Laetsch and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

E.C., M.S. and A.D. made substantial contributions to each stage of the preparation of this manuscript for publication.

Corresponding author

Correspondence to Alexander Drilon.

Ethics declarations

Competing interests

A.D. has received honoraria (as an advisory board member) from Bayer, Ignyta, Loxo Oncology, Pfizer, Roche/Genentech and TP Therapeutics, and research funding from Loxo Oncology. M.S. has received research funding from Daiichi Sankyo and Puma Biotechnology. E.C. declares no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cocco, E., Scaltriti, M. & Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 15, 731–747 (2018). https://doi.org/10.1038/s41571-018-0113-0

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing